Perioperative Marinobufagenin (MBG) Measurement May Improve Acute Kidney Injury Risk Assessment in Patients Undergoing Major Cardiac Surgery: A Proof-of-Concept Study.

Background and Objectives: Acute kidney injury (AKI) remains a significant complication following major cardiac surgery. Marinobufagenin (MBG), a cardiotonic steroid involved in sodium balance and blood pressure regulation, has been linked to organ damage after ischemia-reperfusion events. This pilot, prospective study investigates the utility of circulating MBG to improve AKI risk assessment in cardiac surgery patients as a stand-alone biomarker and after inclusion in a validated risk model (STS-AKI score). Materials and Methods: We included 45 patients undergoing elective cardiac surgery. The MBG levels were measured preoperatively and at 4, 8, and 12 h post-surgery. The AKI was defined according to the KDIGO guidelines. Statistical analyses assessed the diagnostic and prognostic utility of MBG and its integration with the STS-AKI score. Results: An AKI occurred in 26.7% of the patients. The STS-AKI score performed well in this cohort (AUC: 0.736). The MBG levels displayed a decreasing trend in the whole population after surgery (p = 0.02). However, in the AKI patients, MBG increased at 4 and 8 h before decreasing at 12 h post-surgery. The MBG changes from the baseline to 8 h and from 8 to 12 h post-surgery showed a remarkable diagnostic accuracy for an AKI (AUCs: 0.917 and 0.843, respectively). Integrating these MBG changes with the STS-AKI score significantly improved the model performance, including discrimination, calibration, and risk reclassification. Conclusions: The MBG measurement, particularly any dynamic changes post-surgery, enhances AKI risk stratification in cardiac surgery patients. Integrating MBG with the STS-AKI score offers more accurate risk predictions, potentially leading to better patient management and outcomes.

Selenoprotein-P1 (SEPP1) Expression in Human Proximal Tubule Cells after Ischemia-Reperfusion Injury: An In Vitro Model.

Background and Objectives: Selenium deficiency represents a risk factor for the occurrence of severe diseases, such as acute kidney injury (AKI). Recently, selenoprotein-p1 (SEPP1), a selenium transporter, mainly released by the liver, has emerged as a promising plasmatic biomarker of AKI as a consequence of cardio-surgery operations. The aim of the present study was to investigate, on an in vitro model of hypoxia induced in renal tubular cells, HK-2, the effects of sodium selenite (Na2SeO3) and to evaluate the expression of SEPP1 as a marker of injury. Materials and Methods: HK-2 cells were pre-incubated with 100 nM Na2SeO3 for 24 h, and then, treated for 24 h with CoCl2 (500 µM), a chemical hypoxia inducer. The results were derived from an ROS assay, MTT, and Western blot analysis. Results: The pre-treatment determined an increase in cells' viability and a reduction in reactive oxygen species (ROS), as shown by MTT and the ROS assay. Moreover, by Western blot an increase in SEPP1 expression was observed after hypoxic injury as after adding sodium selenite. Conclusions: Our preliminary results shed light on the possible role of selenium supplementation as a means to prevent oxidative damage and to increase SEPP1 after acute kidney injury. In our in vitro model, SEPP1 emerges as a promising biomarker of kidney injury, although further studies in vivo are necessary to validate our findings.

Selenoprotein P-1 (SEPP1) as an Early Biomarker of Myocardial Injury in Patients Undergoing Cardiopulmonary Bypass.

Background: Biomarkers development for prognostication or prediction of perioperative myocardial disease is critical for the evolution of treatment options in patients undergoing cardiac surgery. The aim of our prospective monocentric study was to investigate the role of selenoprotein 1 (SEEP 1) as a potential biomarker for assessing the risk of myocardial injury after cardiac surgery. Methods: Circulating SEPP1 was measured in the blood of 45 patients before surgery and at 4 h, 8 h and 12 h after CPB by enzyme-linked immunosorbent assay (ELISA); (3) Results: circulating SEPP-1 levels measured 4 h after surgery were strongly correlated with CK-MB levels measured at 48 h (R = 0.598, p < 0.0001) and at 72 h (R = 0.308, p = 0.05). Close correlations were also found between 4 h SEPP-1 and Hs-c troponin values measured at 24 h (R = 0.532, p < 0.0001), 48 h (R = 0.348, p = 0.01) and 72 h (R = 0.377, p = 0.02), as well as with cardiopulmonary bypass (CPB) (R = 0.389, p = 0.008) and cross-clamp time (R = 0.374, p = 0.001); (4) Conclusions: Early SEPP1 measurement after CPB may hold great potential for identifying cardiac surgery patients at risk of developing perioperative myocardial injury.

Hypoxia-inducible factor prolyl hydroxylase inhibitors for anaemia in chronic kidney disease: a document by the European Renal Best Practice board of the European Renal Association.

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with poor long-term outcomes and quality of life. The use of supplemental iron, erythropoiesis stimulating agents (ESAs) and blood transfusions has been the mainstay of treatment of anaemia in CKD for more than three decades. Despite available treatments, CKD patients with anaemia are undertreated and moderate-to-severe anaemia remains prevalent in the CKD population. Anaemia has consistently been associated with greater mortality, hospitalisation, cardiovascular events, and CKD progression in patients with CKD, and the risk increases with anaemia severity. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) inhibitors have a novel mechanism of action by mimicking the body's response to hypoxia and have emerged as an alternative to ESAs for the treatment of anaemia in CKD. Their efficacy in correcting and maintaining haemoglobin has been demonstrated in over 30 phase 3 clinical trials. Additionally, HIF activation results in various pleiotropic effects beyond erythropoiesis with cholesterol reduction and improved iron homeostasis and potential anti-inflammatory effects. The long-term safety of these agents, particularly with respect to cardiovascular and thromboembolic events, and their possible effect on tumor growth requires to be fully elucidated. This document presents in detail the effects of HIF-PH inhibitors, describes their mechanisms of action and pharmacologic properties, and discusses their place in the treatment of anaemia in CKD according to the available evidence.

Urinary Post-Translationally Modified Fetuin-A (uPTM-FetA) in Chronic Kidney Disease Patients with and without Diabetic Kidney Disease.

Background and Objectives: A novel post-translational modification (PTM) fragment derived from the cleavage of Fetuin-A (PTM-FetA) has recently emerged as a sensitive biomarker for kidney damage in diabetic patients, but evidence in other chronic renal diseases is lacking. In this pilot study, we aimed at evaluating the clinical significance of urinary PTM-FetA (uPTM-FetA) in a mixed cohort of patients with non-advanced chronic kidney disease (CKD) secondary to diabetic kidney disease (DKD) or other causes. Materials and Methods: We enrolled 47 adult patients with CKD (mean CKD-Epi 40.10 ± 16.5 mL/min/1.73 m2) due to DKD (n = 34) or other etiology (n = 13). uPTM-FetA was measured in the urine using a commercially available ELISA kit. Fifteen healthy individuals served as controls. Results: Collectively, all CKD patients displayed remarkably higher levels of uPTM-FetA than controls (0.84 [0.10-1.15] vs. 29.68 [2.50-55.16] ng/mL p = 0.0005), but values were lower in non-DKD than in DKD patients (1.66 [0.09-4.19] vs. 13.9 [0.01-45.02] ng/mL; p = 0.01). uPTM-FetA showed a great diagnostic capacity at ROC analyses to identify the presence of CKD (AUC 0.776; p < 0.001) and, within CKD patients, to discriminate the diabetic and non-diabetic etiology (AUC 0.673; p = 0.02). At multivariate correlation analyses, proteinuria (ß = 0.442; p = 0.02) and BMI (ß = -0.334; p = 0.04) were the sole independent predictors of uPTM-FetA in this study population. Conclusions: uPTM-FetA could be a novel sensitive biomarker at the crossroad of chronic renal damage and metabolic dysfunction. Additionally, this biomarker could also represent a non-invasive, complementary tool for discriminating among different CKD etiologies (DKD vs. non-DKD) in difficult cases or when renal biopsy is not available.

Spice Up Your Kidney: A Review on the Effects of Capsaicin in Renal Physiology and Disease.

Capsaicin, the organic compound which attributes the spicy flavor and taste of red peppers and chili peppers, has been extensively studied for centuries as a potential natural remedy for the treatment of several illnesses. Indeed, this compound exerts well-known systemic pleiotropic effects and may thus bring important benefits against various pathological conditions like neuropathic pain, rhinitis, itching, or chronic inflammation. Yet, little is known about the possible biological activity of capsaicin at the kidney level, as this aspect has only been addressed by sparse experimental investigations. In this paper, we aimed to review the available evidence focusing specifically on the effects of capsaicin on renal physiology, as well as its potential benefits for the treatment of various kidney disorders. Capsaicin may indeed modulate various aspects of renal function and renal nervous activity. On the other hand, the observed experimental benefits in preventing acute kidney injury, slowing down the progression of diabetic and chronic kidney disease, ameliorating hypertension, and even delaying renal cancer growth may set the stage for future human trials of capsaicin administration as an adjuvant or preventive therapy for different, difficult-to-treat renal diseases.

New Insights on the Role of Marinobufagenin from Bench to Bedside in Cardiovascular and Kidney Diseases.

Marinobufagenin (MBG) is a member of the bufadienolide family of compounds, which are natural cardiac glycosides found in a variety of animal species, including man, which have different physiological and biochemical functions but have a common action on the inhibition of the adenosine triphosphatase sodium-potassium pump (Na+/K+-ATPase). MBG acts as an endogenous cardiotonic steroid, and in the last decade, its role as a pathogenic factor in various human diseases has emerged. In this paper, we have collated major evidence regarding the biological characteristics and functions of MBG and its implications in human pathology. This review focused on MBG involvement in chronic kidney disease, including end-stage renal disease, cardiovascular diseases, sex and gender medicine, and its actions on the nervous and immune systems. The role of MBG in pathogenesis and the development of a wide range of pathological conditions indicate that this endogenous peptide could be used in the future as a diagnostic biomarker and/or therapeutic target, opening important avenues of scientific research.

A Rare Complication of Ascariasis: A Case of Acute Interstitial Nephritis.

Acute interstitial nephritis (AIN) due to helminths is a rare cause of acute kidney injury (AKI). Helminthiases often progresses insidiously, making diagnosis difficult. This was the case of a 72-year-old man, who presented with renal failure, itching and diarrhoea. Urinalysis revealed leukocyturia, microhaematuria and mild proteinuria. A full blood count revealed leucocytosis with eosinophilia. A stool parasitological examination revealed fertilised eggs of Ascaris lumbricoides. Tubulointerstitial nephropathy secondary to A. lumbricoides infection was suspected. A percutaneous renal biopsy was not performed since the patient refused the anti-platelet therapy discontinuation. Mebendazole, albendazole and prednisone therapy was administered. After worm eradiation and discharge, recovery from the parasitosis, absence of pruritus and eosinophilia, and progressive improvement of renal function were observed, strongly suggesting a causal relationship between Ascaris infection and AIN. Parasite infection should be considered in the differential diagnosis of unexplained renal failure because early diagnosis and treatment are necessary to avoid irreversible complications.

Circulating Omentin-1 levels and altered iron balance in chronic haemodialysis patients.

BACKGROUND: Iron deficiency is highly prevalent among patients undergoing chronic haemodialysis (HD) but its correct identification is often problematic as common biomarkers of iron status, such as transferrin saturation (TSAT) and ferritin, can be altered by inflammation or malnutrition. METHODS: In this pilot multicentre study, we aimed at evaluating circulating levels of Omentin-1, a novel fat depot-specific adipokine that is also involved in iron regulation, in a cohort of 85 chronic HD patients with relation to their iron status. RESULTS: Omentin-1 levels in HD were statistically higher than in healthy controls (P = 0.03) and there was a significant, growing trend in all iron parameters across Omentin-1 tertiles (P < 0.001). Compared with patients with optimal iron status, Omentin-1 levels were lower in subjects categorized according to TSAT ≤20% or serum ferritin ≤200 µg/L (both P < 0.001) and even more reduced in 19 patients (22%) simultaneously displaying low levels of both markers (P < 0.001). In this latter group, Omentin-1 levels increased in parallel to all other iron markers after iron correction by i.v. supplementation. At multivariate regression analyses, ferritin (ß = 0.71; P < 0.001) and TSAT (ß = 0.32; P = 0.03) remained the sole independent predictors of Omentin-1 levels. This biomarker also showed a remarkable diagnostic capacity at receiver operating characteristic analyses in identifying iron-depleted HD patients according to a criterion of TSAT ≤20% [area under the curve (AUC) 0.827], ferritin ≤200 µg/L (AUC 0.863) or low levels of both parameters (AUC 0.907). CONCLUSIONS: Findings obtained indicate that Omentin-1 is somewhat involved in iron balance regulation and might be a candidate biomarker for diagnosing and managing altered iron conditions in HD patients.

Autosomic dominant polycystic kidney disease and metformin: Old knowledge and new insights on retarding progression of chronic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common congenital kidney disorder, generally caused by mutations in the PKD1 and PKD2 genes, coding for polycystins 1 and 2. Its pathogenesis is accompanied by alterations of the cAMP, mTOR, MAPK/ERK, and JAK/STAT pathways. ADPKD is clinically characterized by the formation of many growing cysts with kidney enlargement and a progressive damage to the parenchyma, up to its complete loss of function, and the onset of end-stage renal disease (ESRD). The current aim of ADPKD therapy is the inhibition of cyst development and retardation of chronic kidney disease progression. Several drugs have been recently included as potential therapies for ADPKD including metformin, the drug of choice for the treatment of type 2 diabetes mellitus, according to its potential inhibitory effects on cystogenesis. In this review, we summarize preclinical and clinical evidence endorsing or rejecting metformin administration in ADPKD evolution and pathological mechanisms. We explored the biology of APDKD and the role of metformin in slowing down cystogenesis searching PubMed and Clinical Trials to identify relevant data from the database inception to December 2020. From our research analysis, evidence for metformin as emerging cure for ADPKD mainly arise from preclinical studies. In fact, clinical studies are still scanty and stronger evidence is awaited. Its effects are likely mediated by inhibition of the ERK pathway and increase of AMPK levels, which are both linked to ADPKD pathogenesis.

Selenoprotein P-1 (SEPP1) as an Early Biomarker of Acute Kidney Injury in Patients Undergoing Cardiopulmonary Bypass.

Background: Acute Kidney Injury (AKI) is a frequent, dangerous complication in patients undergoing cardiopulmonary bypass (CPB) with oxidative stress playing a crucial role. In this pilot study we evaluated the possible role of the selenoprotein-p1 (SEPP1), a circulating, anti-oxidant selenium transporter, as a predictive biomarker of AKI in this population setting. Methods: Circulating SEPP1 was measured in the blood of 45 patients before surgery and at 4 h, 8 h and 12 h after CPB by Enzyme-Linked Immunosorbent Assay (ELISA). Results: SEPP1 increased from 69 [IQR 39-85] to 3263 [IQR 1886.2-5042.7] ng/mL (p for trend < 0.0001). AKI occurred in 26.7% of patients. In these individuals, an earlier and more prominent increase in SEPP1 was observed at 4 h and 8 h, as compared with those not experiencing AKI (difference between trends p < 0.0001). Logistic regression analyses evidenced 4 h and 8 h SEPP1 as significantly associated with AKI (OR 1.035; 95% CI 1.002-1.068; p = 0.03 and 1.011; 95% CI 1.002-1.021; p = 0.02, respectively). ROC analyses displayed a remarkable discriminatory capacity of early SEPP1 measurements in identifying AKI (AUCs ranging from 0.682 to 0.854; p from 0.04 to < 0.0001). In addition, 12 h-SEPP1 showed diagnostic capacity to identify patients reaching a secondary composite endpoint including major adverse kidney events (MAKEs). Conclusions: Findings from this pilot, exploratory study suggest that early SEPP1 measurement after CPB may hold great potential for improving renal risk stratification in cardiac surgery patients. Further studies in wider and more heterogeneous cohorts are needed to generalize these findings and to evaluate a possible applicability in daily practice.

Decreased Cathepsin-K Mirrors the Severity of Subclinical Atherosclerosis in Kidney Transplant Recipients.

Background: In kidney transplantation (Ktx) recipients, cardiovascular (CV) disease remains the leading cause of death. Abnormal carotid intima-media thickness (IMT) represents a valid indicator of incipient atherosclerosis also in this setting. Cathepsin-K (CatK) is a cysteine protease involved in vascular remodelling, as well as in progressive atherosclerosis. In this study we evaluated clinical predictors of CatK in Ktx recipients, with a particular focus on its possible relationships with subclinical atherosclerosis. Methods: Circulating CatK was measured in 40 stable Ktx recipients together with several laboratory, clinical and echocardiography parameters. 30 healthy subjects and 30 hemodialysis (HD) patients served as controls for CatK values. Carotid IMT was measured in Ktx and these subjects were then categorized according to age-gender reference cut-offs of normal IMT. Results: CatK levels were similar in Ktx recipients and healthy subjects but significantly reduced as compared to HD (p = 0.0001). In Ktx, at multivariate analyses CatK was associated with the LV end-diastolic volume (LVEDVi) ( ß = 0.514; p = 0.05), Ktx vintage ( ß = -0.333; p = 0.05) and mean IMT ( ß = -0.545; p = 0.05); this latter robust inverse association was confirmed also in another multivariate model with IMT as the dependent variable. Logistic regression analyses confirmed the beneficial meaning of CatK increase towards subclinical atherosclerosis [Odds Ratio (OR) 0.761; 95% Confidence Interval (CI) 0.569-0.918, p = 0.04]. At Receiver Operating Characteristics (ROC) analyses, CatK held a remarkable discriminatory power in identifying Ktx patients with abnormally increased IMT [Area Under the Curve (AUC) 0.763; 95% CI 0.601-0.926; p = 0.001]). Conclusions: In Ktx recipients, reduced CatK levels reflect the time-dependent improvement in the uremic milieu, cardiac adaptations and, above all, the severity of subclinical atherosclerosis. CatK measurement in Ktx may therefore hold significance for improving early CV risk stratification.

Hypoxia-Inducible Factor Stabilizers in End Stage Kidney Disease: "Can the Promise Be Kept?"

Anemia is a common complication of chronic kidney disease (CKD). The prevalence of anemia in CKD strongly increases as the estimated Glomerular Filtration Rate (eGFR) decreases. The pathophysiology of anemia in CKD is complex. The main causes are erythropoietin (EPO) deficiency and functional iron deficiency (FID). The administration of injectable preparations of recombinant erythropoiesis-stimulating agents (ESAs), especially epoetin and darbepoetin, coupled with oral or intravenous(iv) iron supplementation, is the current treatment for anemia in CKD for both dialysis and non-dialysis patients. This approach reduces patients' dependence on transfusion, ensuring the achievement of optimal hemoglobin target levels. However, there is still no evidence that treating anemia with ESAs can significantly reduce the risk of cardiovascular events. Meanwhile, iv iron supplementation causes an increased risk of allergic reactions, gastrointestinal side effects, infection, and cardiovascular events. Currently, there are no studies defining the best strategy for using ESAs to minimize possible risks. One class of agents under evaluation, known as prolyl hydroxylase inhibitors (PHIs), acts to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. Several randomized controlled trials showed that HIF-PHIs are almost comparable to ESAs. In the era of personalized medicine, it is possible to envisage and investigate specific contexts of the application of HIF stabilizers based on the individual risk profile and mechanism of action.

Retarding Progression of Chronic Kidney Disease in Autosomal Dominant Polycystic Kidney Disease with Metformin and Other Therapies: An Update of New Insights.

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent single-gene disorder leading to renal failure. Current therapies are aimed to treat renal and extrarenal complications of ADPKD, but improved knowledge of the pathophysiological mechanisms leading to the generation and growth of cysts has permitted the identification of new drug candidates for clinical trials. Among these, in this review, we will examine above all the role of metformin, hypothesized to be able to activate the AMP-activated protein kinase (AMPK) pathway and potentially modulate some mechanisms implicated in the onset and the growth of the cysts.

Smoking habit as a risk amplifier in chronic kidney disease patients.

Several studies showed the association between non-traditional risk factors [proteinuria and estimated Glomerular Filtration Rate (eGFR)] and cardiovascular (CV) and renal outcomes. Nevertheless, the etiologic role of traditional CV risk factors in referred CKD patients is less defined. Herein, we examined the association between smoking habit and CV events, mortality and CKD progression. We undertook an observational analysis of 1306 stage III-V CKD patients. Smoking habit was modeled as a categorical (never, current or former smokers) and continuous (number of cigarettes/day) variable. Mean eGFR was 35.8 ± 12.5 mL/min/1.73 m2. Never, current and former smokers were 61.1%, 10.8% and 28.1%. During a median follow-up of 2.87 years, current and former smokers were at significant risk for CV events (HRs of 1.93 [95% CI, 1.18-3.16] and 1.44 [95% CI, 1.01-2.05]) versus never smokers. Current smokers were at increased mortality risk (HR 2.13 [95% CI, 1.10-4.11]). Interactions were found between former smokers and proteinuria (p = 0.007) and diabetes (p = 0.041) for renal risk, and between current smokers and male gender (p = 0.044) and CKD stage V (p = 0.039) for renal and mortality risk. In referred CKD patients, smoking habit is independently associated with CV events and mortality. It acts as a risk "amplifier" for the association between other risk factors and renal outcomes.

Nephrosclerosis impacts time trajectory of renal function and outcomes in elderly individuals with chronic kidney disease.

Despite hypertension ranks among the leading causes of chronic kidney disease (CKD), the impact of chronic hypertensive nephropathy, the so-called 'nephrosclerosis' (NS), on CKD progression is often unpredictable, particularly in elderly population. We have conducted a prospective, observational study to define renal function patterns and outcomes in elderly CKD individuals with or without NS. Three hundred four individuals with an already established CKD were categorized according to the etiology of CKD. NS was defined as the presence of CKD associated with long-term essential hypertension, hypertensive retinopathy, left ventricular hypertrophy and minimal proteinuria. Time trajectories in estimated glomerular filtration rate (eGFR) (CKD-Epi) were computed over a 4-year follow-up. In addition, we analyzed the occurrence of a composite outcome of doubling of serum creatinine levels, eGFR reduction ≥25% and/or the need of chronic renal replacement therapy. CKD was secondary to nephrosclerosis (CKD-NS) in 220 (72.3%). In the whole cohort, the average estimated annual GFR slope was 1.8 mL/min/1.73 m2 eGFR decline was slower in CKD-NS as compared with others (1.4 vs 3.4 mL/min/1.73 m2; p<0.001). The composite renal outcome during follow-up occurred less frequently among elderly with CKD-NS (16/204 vs 14/70; p=0.01, crude HR 0.43, 95% CI 0.22 to 0.85) and was associated at logistic analyses with the etiology of CKD, background cardiovascular disease, total and low density lipoproteins (LDL) cholesterol, and glycemia levels (p value was ranging from 0.01 to 0.05). Despite being highly prevalent in the elderly, NS is associated with a more favorable renal disease course as compared with other conditions.

Antecedent ACE-inhibition, inflammatory response, and cardiac surgery associated acute kidney injury.

Cardiopulmonary bypass (CPB) may trigger organs damage, including kidney injury, due to a massive cytokine release. In this observational, prospective study, we analyzed the possible impact of chronic treatment with ACE-Inhibitors (ACE-I) on the inflammatory response and renal function after CPB. Sixty-nine patients undergoing major cardiac surgery with CPB were enrolled. Patients were stratified according to long-term (> 6 mo.) ACE-I use (n = 38) or not (n = 31). The primary endpoint was the change in IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, TNF alpha, EGF and VEGF plasma levels. Secondary (renal) endpoints were postoperative acute kidney injury (AKI), recovery of baseline GFR values and the absolute changes in renal function indexes. After CPB, IL-1alpha, IL-1beta, IL-4 and TNF-alpha remained stable over time while a significant decrease in IL-2 levels was noticed in the ACE-I group (p = 0.01). IL-6 and IL-8 increased after surgery and tended to decrease after 48 h. IL-10 levels showed a similar variation, but both their rise and decrease were more pronounced in patients under ACE-I treatment (p = 0.007). Finally, VEGF and EGF showed a marked initial decrease with a tendency to normalization 10 days after surgery (p for trend ranging from 0.01 to 0.001). The occurrence of AKI within 2 days after surgery, the rate of GFR recovery and the absolute changes in renal function indexes were not statistically different between groups. Chronic, long-term ACE-I treatment may influence the inflammatory response following CPB. On the other hand, this drug class apparently has neutral impact on perioperative renal outcomes.

Increased circulating Cathepsin-K levels reflect PTH control in chronic hemodialysis patients.

BACKGROUND: Mineral bone disease (MBD) is remarkably frequent among chronic hemodialysis (HD) patients. In this setting, deranged PTH levels portend an adjunctive risk of worsen outcomes. Various evidence exists demonstrating that PTH strongly induces Cathepsin-K, a cysteine protease mainly found in lysosomes of osteoclasts and macrophages which promotes bone and extracellular matrix remodelling. Cathepsin-K levels are altered in various bone disorders, systemic inflammation and even in non-advanced CKD. In this study, we tested the hypothesis of an association between Cathepsin-K, uremic-MBD and circulating PTH levels in a cohort of chronic HD patients. METHODS: We measured Cathepsin-K in 85 stable chronic HD patients and dialysis vintage > 6 months by a commercially available ELISA kit and we collected routine clinical parameters, including intact PTH. Patients were further stratified according to their "on- target" or "off-target" PTH status. RESULTS: Cathepsin-K levels were significantly higher in HD patients than in healthy controls (p < 0.0001) and were independently associated with alkaline phosphatase (ß = 0.37; p < 0.001), PTH (ß = 0.30; p = 0.02) and C-reactive protein (ß = 0.24; p = 0.008) levels. Cathepsin-K was also higher in patients with off-target PTH as compared to those with controlled PTH levels (230 [40-420] vs. 3250 [820-4205] pg/mL; p < 0.0001). At ROC analyses, Cathepsin-K levels were able to identify off-target PTH and parathyroidectomized patients (AUCs 0.85 [95% CI 0.71-0.98] and 0.97 [95% CI 0.92-0.99], respectively). CONCLUSION: In chronic HD patients, Cathepsin-K associates with PTH levels, raising the intriguing hypothesis that this protein represents a causal link between mineral and inflammatory complications and could be tested as a candidate biomarker of MBD severity and PTH balance.

Cathepsin-K is a potential cardiovascular risk biomarker in prevalent hemodialysis patients.

PURPOSE: Cardiovascular (CV) disease remains the leading cause of mortality among end-stage kidney disease (ESKD) patients. Cathepsin-K (CatK), a small cysteine protease involved in bone and extracellular matrix remodeling, has recently emerged as a key-factor in the pathogenesis of various conditions predisposing to CV disease, including atherosclerosis, obesity, diabetes, and vascular calcification. In this pilot prospective study, we aimed at evaluating the clinical significance and the predictive power of CatK in a small cohort of hemodialysis (HD) patients. METHODS: Cathepsin-K was measured in 54 prevalent HD patients and in 30 controls together with routine parameters. Patients were then followed up to 26 months and the time of cardiovascular death (endpoint of the study prospective phase) recorded. RESULTS: CatK levels were increased in the HD cohort as compared with controls (p < 0.001). In HD patients, CatK was also independently correlated to PTH (ß = 0.368; p = 0.001), alkaline phosphatase (ß = 0.383; p < 0.001), C-reactive protein (ß = 0.260; p = 0.01), and white cell count (ß = - 0.219; p = 0.02). After baseline assessment, patients were followed for CV death (mean follow-up 24.8 ± 3.1 months). Kaplan-Meier analysis showed a worsen survival (log-rank p = 0.04) in HD patients with CatK levels > 440 pg/mL (best ROC-derived cut-off with 69.6% sensitivity and 79.8% specificity) with a crude HR (Mantel-Haenszel) of CV death of 3.46 (95% CI 1.89-13.44). CONCLUSIONS: In prevalent HD patients, altered CatK levels may reflect mineral dysmetabolism and inflammation, and predict CV death in the mid-term. These preliminary findings prompt the rationale for further investigations on larger cohorts to validate CatK as a biomarker for improving CV risk stratification in ESKD.

Aldosterone antagonists in addition to renin angiotensin system antagonists for preventing the progression of chronic kidney disease.

BACKGROUND: Treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) is used to reduce proteinuria and retard the progression of chronic kidney disease (CKD). However, resolution of proteinuria may be incomplete with these therapies and the addition of an aldosterone antagonist may be added to further prevent progression of CKD. This is an update of a Cochrane review first published in 2009 and updated in 2014. OBJECTIVES: To evaluate the effects of aldosterone antagonists (selective (eplerenone), non-selective (spironolactone or canrenone), or non-steroidal mineralocorticoid antagonists (finerenone)) in adults who have CKD with proteinuria (nephrotic and non-nephrotic range) on: patient-centred endpoints including kidney failure (previously know as end-stage kidney disease (ESKD)), major cardiovascular events, and death (any cause); kidney function (proteinuria, estimated glomerular filtration rate (eGFR), and doubling of serum creatinine); blood pressure; and adverse events (including hyperkalaemia, acute kidney injury, and gynaecomastia). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 13 January 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared aldosterone antagonists in combination with ACEi or ARB (or both) to other anti-hypertensive strategies or placebo in participants with proteinuric CKD. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. Data were summarised using random effects meta-analysis. We expressed summary treatment estimates as a risk ratio (RR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, or standardised mean difference (SMD) when different scales were used together with their 95% confidence interval (CI). Risk of bias were assessed using the Cochrane tool. Evidence certainty was evaluated using GRADE. MAIN RESULTS: Forty-four studies (5745 participants) were included. Risk of bias in the evaluated methodological domains were unclear or high risk in most studies. Adequate random sequence generation was present in 12 studies, allocation concealment in five studies, blinding of participant and investigators in 18 studies, blinding of outcome assessment in 15 studies, and complete outcome reporting in 24 studies. All studies comparing aldosterone antagonists to placebo or standard care were used in addition to an ACEi or ARB (or both). None of the studies were powered to detect differences in patient-level outcomes including kidney failure, major cardiovascular events or death. Aldosterone antagonists had uncertain effects on kidney failure (2 studies, 84 participants: RR 3.00, 95% CI 0.33 to 27.65, I² = 0%; very low certainty evidence), death (3 studies, 421 participants: RR 0.58, 95% CI 0.10 to 3.50, I² = 0%; low certainty evidence), and cardiovascular events (3 studies, 1067 participants: RR 0.95, 95% CI 0.26 to 3.56; I² = 42%; low certainty evidence) compared to placebo or standard care. Aldosterone antagonists may reduce protein excretion (14 studies, 1193 participants: SMD -0.51, 95% CI -0.82 to -0.20, I² = 82%; very low certainty evidence), eGFR (13 studies, 1165 participants, MD -3.00 mL/min/1.73 m², 95% CI -5.51 to -0.49, I² = 0%, low certainty evidence) and systolic blood pressure (14 studies, 911 participants: MD -4.98 mmHg, 95% CI -8.22 to -1.75, I² = 87%; very low certainty evidence) compared to placebo or standard care. Aldosterone antagonists probably increase the risk of hyperkalaemia (17 studies, 3001 participants: RR 2.17, 95% CI 1.47 to 3.22, I² = 0%; moderate certainty evidence), acute kidney injury (5 studies, 1446 participants: RR 2.04, 95% CI 1.05 to 3.97, I² = 0%; moderate certainty evidence), and gynaecomastia (4 studies, 281 participants: RR 5.14, 95% CI 1.14 to 23.23, I² = 0%; moderate certainty evidence) compared to placebo or standard care. Non-selective aldosterone antagonists plus ACEi or ARB had uncertain effects on protein excretion (2 studies, 139 participants: SMD -1.59, 95% CI -3.80 to 0.62, I² = 93%; very low certainty evidence) but may increase serum potassium (2 studies, 121 participants: MD 0.31 mEq/L, 95% CI 0.17 to 0.45, I² = 0%; low certainty evidence) compared to diuretics plus ACEi or ARB. Selective aldosterone antagonists may increase the risk of hyperkalaemia (2 studies, 500 participants: RR 1.62, 95% CI 0.66 to 3.95, I² = 0%; low certainty evidence) compared ACEi or ARB (or both). There were insufficient studies to perform meta-analyses for the comparison between non-selective aldosterone antagonists and calcium channel blockers, selective aldosterone antagonists plus ACEi or ARB (or both) and nitrate plus ACEi or ARB (or both), and non-steroidal mineralocorticoid antagonists and selective aldosterone antagonists. AUTHORS' CONCLUSIONS: The effects of aldosterone antagonists when added to ACEi or ARB (or both) on the risks of death, major cardiovascular events, and kidney failure in people with proteinuric CKD are uncertain. Aldosterone antagonists may reduce proteinuria, eGFR, and systolic blood pressure in adults who have mild to moderate CKD but may increase the risk of hyperkalaemia, acute kidney injury and gynaecomastia when added to ACEi and/or ARB.